1. Field of Invention
The present invention relates to the transdermal delivery of drugs from a silicone-based polymeric mixture. More particularly the present invention relates to methods and compositions for the controlled transdermal delivery of drugs that are otherwise adversely affecting or affected by silicone-based adhesives, such as basic and amine-functional drugs.
2. Description of Related Art
Delivery of certain drugs transdermally has been known to be theoretically possible for many years. However, only limited commercial exploitation of transdermal drug delivery systems has been achieved due in large part to the many practical problems to be overcome with real systems. These problems include the solubility of the drug in the polymeric or adhesive layer, the effect of the drug on the polymeric or adhesive layer, delivery of the drug to the skin and through the stratum corneum at a constant rate over a prolonged period, and stability of the transdermal drug delivery system during storage prior to use.
In seeking to develop transdermal patches that overcome such practical problems, silicone-based adhesives, particularly pressure-sensitive adhesives, have been employed and many are commercially available. Generally, silicone pressure-sensitive adhesives are produced by either blending or condensing a silicone resin and a polydiorganosiloxane. Silicone pressure-sensitive adhesives are known to be non-irritating and non-sensitizing to the skin which is often not true for other polymer-based adhesives such as acrylics.
Currently, amine compatible silicone pressure-sensitive adhesives are used commercially for transdermal delivery of fentanyl. These systems require the use of ethanol containing reservoirs and rate controlling membranes to achieve controlled drug permeation.
However, fentanyl and other amine-functional drugs including, for example nitroglycerin, scopolamine, clonidine, nicotine, tetracain, ramipril and enalapril, that are desirable to be delivered transdermally can interact with silicone adhesives by acting as catalysts for the condensation of silicone-bonded hydroxyl groups (thereby resulting in loss of cohesivity and adhesivity) or be degraded/destabilized in the presence of such hydroxy groups.
U.S. Pat. No. RE 35,474 teaches that amine-functional drugs interfere with the properties of pressure-sensitive adhesives by catalyzing the reaction of silicone-bonded hydroxyl (silanol) groups and, thereby, cause increased increase shear of the pressure-sensitive adhesive material and, thus, loss of tack during storage. This reference teaches that this effect can be inhibited by chemically treating the pressure-sensitive adhesives with an agent to reduce their silanol content.
U.S. Pat. No. 6,337,086 teaches that the amount of agent used to treat the silicone pressure-sensitive adhesive material as disclosed in U.S. Pat. No. RE 35,474 may result in a silanol content that is too low, and therefore an adhesive that is plasticized and oozy. Accordingly, to achieve the adhesive performance properties (i.e., peel and shear) necessary for transdermal applications, such silicone pressure-sensitive adhesive materials must be prepared with well-defined silanol concentrations.
However, in formulating a simplified drug-in-adhesive transdermal system (i.e., wherein the adhesive functions as both the drug carrier and means of attachment to the topical application site), incorporating fentanyl directly into an amine compatible silicone pressure-sensitive adhesive results in crystallization of the drug and therefore loss of bioavailability.
Therefore, it would be advantageous to find a silicone-based adhesive system that can solubilize sufficient amounts of drugs that are otherwise adversely affecting or affected by such silicone-based adhesives, and that can permit drug release in a controlled fashion over a prolonged period at a steady rate of delivery.